دورية أكاديمية
The Discovery of Two Novel Classes of 5,5-Bicyclic Nucleoside-Derived PRMT5 Inhibitors for the Treatment of Cancer.
| العنوان: | The Discovery of Two Novel Classes of 5,5-Bicyclic Nucleoside-Derived PRMT5 Inhibitors for the Treatment of Cancer. |
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| المؤلفون: | Quiroz RV; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Reutershan MH; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Schneider SE; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Sloman D; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Lacey BM; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Swalm BM; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Yeung CS; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Gibeau C; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Spellman DS; Merck & Co., Inc., 770 Sumneytown Pike, Lansdale, Pennsylvania 19446, United States., Rankic DA; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Chen D; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Witter D; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Linn D; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Munsell E; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Feng G; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Xu H; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Hughes JME; Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Lim J; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Saurí J; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Geddes K; Merck & Co., Inc., 770 Sumneytown Pike, Lansdale, Pennsylvania 19446, United States., Wan M; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Mansueto MS; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Follmer NE; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Fier PS; Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Siliphaivanh P; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Daublain P; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Palte RL; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Hayes RP; Merck & Co., Inc., 770 Sumneytown Pike, Lansdale, Pennsylvania 19446, United States., Lee S; Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Kawamura S; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Silverman S; Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States., Sanyal S; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Henderson TJ; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Ye Y; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Gao Y; Merck & Co., Inc., 770 Sumneytown Pike, Lansdale, Pennsylvania 19446, United States., Nicholson B; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Machacek MR; Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2021 Apr 08; Vol. 64 (7), pp. 3911-3939. Date of Electronic Publication: 2021 Mar 23. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | Aminoquinolines/*therapeutic use , Antineoplastic Agents/*therapeutic use , Enzyme Inhibitors/*therapeutic use , Neoplasms/*drug therapy , Nucleosides/*therapeutic use , Protein-Arginine N-Methyltransferases/*antagonists & inhibitors, Aminoquinolines/chemical synthesis ; Aminoquinolines/metabolism ; Animals ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/metabolism ; Cell Proliferation/drug effects ; Drug Design ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/metabolism ; Female ; Humans ; Mice, SCID ; Molecular Docking Simulation ; Molecular Structure ; Nucleosides/chemical synthesis ; Nucleosides/metabolism ; Protein Binding ; Protein-Arginine N-Methyltransferases/metabolism ; Structure-Activity Relationship ; Mice |
| مستخلص: | Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the post-translational symmetric dimethylation of protein substrates. PRMT5 plays a critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. As such, dysregulation of PRMT5 activity is implicated in the development and progression of multiple cancers and is a target of growing clinical interest. Described herein are the structure-based drug designs, robust synthetic efforts, and lead optimization strategies toward the identification of two novel 5,5-fused bicyclic nucleoside-derived classes of potent and efficacious PRMT5 inhibitors. Utilization of compound docking and strain energy calculations inspired novel designs, and the development of flexible synthetic approaches enabled access to complex chemotypes with five contiguous stereocenters. Additional efforts in balancing bioavailability, solubility, potency, and CYP3A4 inhibition led to the identification of diverse lead compounds with favorable profiles, promising in vivo activity, and low human dose projections. |
| المشرفين على المادة: | 0 (Aminoquinolines) 0 (Antineoplastic Agents) 0 (Enzyme Inhibitors) 0 (Nucleosides) EC 2.1.1.319 (PRMT5 protein, human) EC 2.1.1.319 (Protein-Arginine N-Methyltransferases) |
| تواريخ الأحداث: | Date Created: 20210323 Date Completed: 20210607 Latest Revision: 20240226 |
| رمز التحديث: | 20240226 |
| DOI: | 10.1021/acs.jmedchem.0c02083 |
| PMID: | 33755451 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.0c02083 |